US4112217A - Bis-hydrazones of daunomycin and adriamycin - Google Patents
Bis-hydrazones of daunomycin and adriamycin Download PDFInfo
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- US4112217A US4112217A US05/830,091 US83009177A US4112217A US 4112217 A US4112217 A US 4112217A US 83009177 A US83009177 A US 83009177A US 4112217 A US4112217 A US 4112217A
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- bis
- daunomycin
- sub
- acid addition
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
Definitions
- the structures of the present invention represent a new class of doubly intercalating derivatives of daunomycin and adriamycin.
- Recent studies from several laboratories [especially that by Canellakis et al., Biophysica Acta, 418, 277-314 (1976)] have demonstrated that this mode of DNA binding is associated with important biological properties (especially cytotoxic and antitumor properties of a series of bis-9-acridyl compounds).
- Use of the helical DNA-adriamycin molecular model which has proven useful in the past in this project, suggested that bis-derivatives of the type disclosed could form a unique doubly intercalated complex.
- n is an integer having a value of from 0 through 8 and the radicals indicated by R and R' each represent hydrogen except that in those instances in which n has a value of 2, the R groups, if not hydrogen, may be methyl radicals (with R' remaining as hydrogen), and the R' groups, if not hydrogen, may be hydroxy radicals (with R remaining as hydrogen), together with their pharmaceutically acceptable acid addition salts.
- acid addition salts are preferably the pharmaceutically acceptable, nontoxic addition salts with suitable acids, such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulphuric and phosphoric acids, and with organic acids, such as organic carboxylic acids, for example, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicyclic acids, and organic sulphonic acids, for example, methanesulphonic and toluene-p-sulphonic acids.
- suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulphuric and phosphoric acids
- organic acids such as organic carboxylic acids, for example, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicyclic acids, and organic sulphonic acids, for example, methanesulphonic and toluene-p-sulphonic acids.
- the compounds are preferably employed in the salt form since they have adequate solubility in water. However, they can be employed in the non-acid condition.
- An acid addition salt can be converted into the free compound according to known methods, for example, by treating it with a base, such as with a metal hydroxide or alkoxide, for example, an alkali metal or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example sodium, potassium or calcium carbonate or hydrogen carbonate; with ammonia; or with a hydroxyl ion exchange resin, or with any other suitable reagent.
- a base such as with a metal hydroxide or alkoxide, for example, an alkali metal or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example sodium, potassium or calcium carbonate or hydrogen carbonate
- An acid addition salt may also be converted into another acid addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, of an acid in a suitable diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium.
- a metal salt for example a sodium, barium or silver salt
- An acid addition salt may also be converted into another acid addition salt by treatment with an anion exchange preparation.
- the compounds of this invention or the salts thereof can be administered by any available route, including oral and parenteral (intravenous, intraperitoneal, subcutaneous, and intramuscular) administration.
- parenteral intravenous, intraperitoneal, subcutaneous, and intramuscular
- the amounts administered are those efficient to ameliorate the cancer.
- the compounds of this invention can readily be prepared by reacting the adriamycin or daunomycin starting materials (in suitable salt form) with the appropriate dihydrazide reactant, the reaction proceeding in an appropriate solvent (e.g., methanol) at room temperatures.
- an appropriate solvent e.g., methanol
- the reactants employed are succindihydrazide and glutardihydrazide, respectively.
- XL-100 NMR DMSOd 6 ( ⁇ 55°), 8-12 ⁇ (v.
- a suspension of 0.564 g (1.0 mmol) of daunomycin hydrochloride and 0.059 g (0.5 mmol) of oxalyl dihydrazide in 200 ml of methanol was stirred at room temperature in the dark. After 15 days, the homogenous reaction mixture was concentrated to 100 ml and stirred at room temperature for an additional 40 days. The reaction mixture was concentrated to 50 ml and then 75 ml of absolute ethanol was added dropwise. The resulting fine gelatinous precipitate was collected by centrifugation (3000 X g); the precipitate was transferred to a fritted disc funnel and washed with 2--2 ml portions of absolute ethanol and with 5 ml of ether.
- Biological testing data for compounds of this invention as the HCl salts, as well as for adriamycin and daunomycin, are presented in the table given below.
- the compounds were tested first in cultured lymphoid leukemia L1210 cells for inhibition of nucleic acid synthesis by previously reported procedures.
- the analogs were then tested against lymphocytic leukemia P388 implanted in mice, under the auspices of the NCI and according to its protocols which use the increased survival time of treated mice compared to controls as the measure of antitumor efficacy.
Abstract
Bis-hydrazones of daunomycin and adriamycin having useful antitumor characteristics and the structure ##STR1## WHEREIN N IS AN INTEGER HAVING A VALUE OF FROM 0 THROUGH 8 AND THE RADICALS INDICATED BY R and R' each represent hydrogen except that in those instances in which n has a value of 2, the R groups, if not hydrogen, may be methyl radicals (with R' remaining as hydrogen), and the R' groups, if not hydrogen, may be hydroxy radicals (with R remaining as hydrogen).
Description
The invention described herein was made in the course of or under a contract with the U.S. Department of Health, Education, and Welfare.
The structures of the present invention represent a new class of doubly intercalating derivatives of daunomycin and adriamycin. Recent studies from several laboratories [especially that by Canellakis et al., Biophysica Acta, 418, 277-314 (1976)] have demonstrated that this mode of DNA binding is associated with important biological properties (especially cytotoxic and antitumor properties of a series of bis-9-acridyl compounds). Use of the helical DNA-adriamycin molecular model, which has proven useful in the past in this project, suggested that bis-derivatives of the type disclosed could form a unique doubly intercalated complex.
The present invention rests on discovery of novel compounds having useful antitumor characteristics which possess the following general structure ##STR2## wherein n is an integer having a value of from 0 through 8 and the radicals indicated by R and R' each represent hydrogen except that in those instances in which n has a value of 2, the R groups, if not hydrogen, may be methyl radicals (with R' remaining as hydrogen), and the R' groups, if not hydrogen, may be hydroxy radicals (with R remaining as hydrogen), together with their pharmaceutically acceptable acid addition salts.
__________________________________________________________________________
Representative compounds which fall within the scope of the present
invention include:
__________________________________________________________________________
R═R'═H,n=2
Bis(daunomycin) Succinylhydrazone Dihydrochloride (I)
R═R'═H,n=3
Bis(daunomycin) Glutarylhydrazone Dihydrochloride (II)
R═R'═H,n=4
Bis(daunomycin) Adipylhydrazone Dihydrochloride (III)
R═R'═H,n=6
Bis(daunomycin) Suberylhydrazone Dihydrochloride (IV)
R═R'═H,n=8
Bis(daunomycin) Sebacylhydrazone Dihydrochloride (V)
R═Me, R'═H,n=2
Bis(N,N-dimethyldaunomycin) Succinylhydrazone Dihydrochloride
(VI)
R═H,R'═OH,n=2
Bis(adriamycin) Succinylhydrazone Dihydrochloride (VII)
R═R'═H,n=1
Bis(daunomycin) Malonylhydrazone Dihydrochloride (VIII)
R═R'═H,n=0
Bis(daunomycin) Oxalylhydrazone Dihydrochloride (IX)
R═R'═H,n=5
Bis(daunomycin) Pimelylhydrazone Dihydrochloride
__________________________________________________________________________
(X)
Compounds (I) through (X) enumerated above form the subject of corresponding examples 1 through 10, said examples including the details of the preparation of each compound as well as its characteristics. It will be noted that these compounds are prepared in the form of an acid addition salt with the free NH2 -or N(CH3)2 - groups of the compounds. These acid addition salts (prepared as those of HCl) are preferably the pharmaceutically acceptable, nontoxic addition salts with suitable acids, such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulphuric and phosphoric acids, and with organic acids, such as organic carboxylic acids, for example, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicyclic acids, and organic sulphonic acids, for example, methanesulphonic and toluene-p-sulphonic acids.
The compounds are preferably employed in the salt form since they have adequate solubility in water. However, they can be employed in the non-acid condition.
An acid addition salt can be converted into the free compound according to known methods, for example, by treating it with a base, such as with a metal hydroxide or alkoxide, for example, an alkali metal or alkaline earth metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example sodium, potassium or calcium carbonate or hydrogen carbonate; with ammonia; or with a hydroxyl ion exchange resin, or with any other suitable reagent.
An acid addition salt may also be converted into another acid addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, of an acid in a suitable diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium. An acid addition salt may also be converted into another acid addition salt by treatment with an anion exchange preparation.
In the treatment of cancer, the compounds of this invention or the salts thereof can be administered by any available route, including oral and parenteral (intravenous, intraperitoneal, subcutaneous, and intramuscular) administration. The amounts administered are those efficient to ameliorate the cancer.
Apart from requiring an extended reaction time, the compounds of this invention can readily be prepared by reacting the adriamycin or daunomycin starting materials (in suitable salt form) with the appropriate dihydrazide reactant, the reaction proceeding in an appropriate solvent (e.g., methanol) at room temperatures. Thus, when n is to have a value of 2 or 3, for example, the reactants employed are succindihydrazide and glutardihydrazide, respectively.
A mixture of 1.13 g (2.0 mmol) of daunomycin hydrochloride (XII) and 0.146 g (1.0 mmol) of succinic acid dihydrazide in 120 ml of methanol was stirred at room temperature in the dark for three days. The reaction mixture was concentrated in vacuo to about 50 ml and then stirred at room temperature for two additional days. To the stirred solution was added 100 ml of ether dropwise; the resulting precipitate was collected, washed with ether and dried. The precipitate was powdered well and redried at room temperature /0.1 mm/16 hr to afford 1.18 g (91%) of (I) as an orange powder, mp decomposes slowly from 216°. IR (Nujol) 3.00, 3.10 μm (OH,NH), 5.95 C═N), 6.15, 6.29 (C═O, chelated quinone), UV-Vis max (CH3 OH) 233 nm (ε = 88,500), 250 sh (55,900), 288 (14,700), 477 (22,000), 495 (21,100), 531 sh (11,800). XL-100 NMR DMSOd6 (˜ 55°) 8.0-14.0 δ (v. broad, OH,N.sup.⊕ H3), 9.50 (bs, 2, NHCO), 7.81 (m, 4, H-1,3), 7.56 (m, 2, H-2), 5.32 (bs, 2, H-1'), 5.10 (s, 4, OH-4', 9), 4.90 (bs, 2, H-7), 4.12 ("d", 2, J=6Hz, H-5'), 3.96 (s, 6, OCH3), 3.64 (bs, 2, H-4'), 3.38 (m, 2, H-3'), 2.98 (m, 4, H-10), 2.37 (bs, 4, (CH2)2), ˜ 2.37 (bs, 2, H-8B), 1.90 (s, 6, H-14), ˜ 1.85 (m, 2, H-8A), 1.80 (m, 4, H-2'), 1.18 (d, 6, J=6Hz, CH3 -5'). [α]D 21° = +247° (c, 0.048, EtOH. Tlc on SiHF CHCl3 /CH3 OH/H2 O (20/10/1 ), (XII) Rf 0.40, (I) Rf 0.04. Paper chromatography on Whatman No. 1 Paper: in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.73, (I) Rf 0.62; in n-PrOH/EtOAc/H2 O (7/1/2) (XII) Rf 0.67, (I) 0.07.
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Anal. Calcd. for C.sub.58 H.sub.64 N.sub.6 O.sub.20 ·2HCl.multido
t.3H.sub.2 O
C H Cl.sup.θ
N
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53.91 5.62 5.49 6.51
Found: 53.81 5.32 5.53 6.61
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A mixture of 1.13 g (2.0 mmol) of daunomycin hydrochloride and 0.160 g (1.0 mmol) of glutaric dihydrazide in 120 ml of methanol was stirred at room temperature in the dark for 3 days. The reaction mixture was concentrated in vacuo to about 50 ml and then stirred at room temperature for two additional days. To the stirred solution was added 125 ml of ether dropwise; the resulting fine precipitate was collected, washed with ether and dried. The precipitate was powdered well and redried at room temperature /0.1 mm/16 hr to afford 1.20 g (93%) of (II) as an orange powder, mp 206°-220° dec. IR (Nujol) 2.98, 3.08 μm (OH,NH), 6.00 (C═N), 6.18, 6.31 (C═O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε = 81,600), 250 sh (51,200), 290 (14,700), 484-492 plateau (19,800), 499 (20,100) 537 sh (11,600). XL-100 NMR DMSOd6 (˜ 50°) 9.0-12.0 δ (v. broad, OH,N.sup.⊕ H3), 9.89 (bs, 2, NHCO), 7.84 (m, 4, H-1,3), 7.60 (m, 2, H-2), 5.23 (bs, 2, H-1'), 4.95 (s, 2, OH), 4.87 (bs, 2, H-7), 4.12 (m, 2, H-5'), 3.98 (s, 6, OCH3), 3.63 (bs, 2, H-4'), ˜ 3.3 (H-3', hidden by H2 O peak), ˜ 3.1 (H-10B, hidden by H2 O peak), 2.91 (d, 2, J=19Hz, H-10A), 2.23 (m, 8, H-8, COCH2 CH2 CH2 CO), 1.94 (s, 6, H-14) ˜ 1.94 (m, 2, COCH2 CH2 CH2 CO), 1.77 (m, 4, H-2'), 1.19 (d, 6, J=7Hz, CH3 -5'). [α]D <° = + 166° (c, 0.052, EtOH). Tlc on SiHF CHCl3 /CH3 OH/H2 O (20/10/1 ), (XII) Rf 0.40 (II) Rf 0.07. Paper chromatography on Whatman No. 1 Paper: in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.73, (II) Rf 0.66; in n-PrOH/EtOAc/H2 O (7/1/2) (XII) Rf 0.67, (II) Rf 0.15.
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Anal. Calcd. for C.sub.59 H.sub.66 N.sub.6 O.sub.20 ·2HCl.multido
t.2 1/2 H.sub.2 O
C H Cl.sup.θ
N
______________________________________
54.63 5.67 5.47 6.48
Found: 54.67 5.45 5.40 6.65
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A mixture of 0.316 g (0.56 mmol) of daunomycin hydrochloride and 0.049 g (0.28 mmol) of adipic acid dihydrazide in 25 ml of methanol was stirred at room temperature in the dark. After 5 days, the reaction mixture was concentrated to 13 ml and then 15 ml of ether was added dropwise. The resulting precipitate was collected, washed with 3-10 ml portions of ether and dried at room temperature /0.1 mm/15 hr to yield the bis-hydrazone dihydrochloride (III), 0.333 g (91%), mp - decomposes gradually 235°-250°. IR (Nujol) 2.82, 3.11 μm (OH), 5.98 C═O, hydrazone), 6.19, 6.31 (C═O, chelated quinone), UV-Vis max (CH3 OH) 233 nm (ε = 83,100), 250 sh (51,100), 289 (14,900), 479-488 plateau (20,300), 489-498 plateau (20,200), 535 sh (11,300). XL-100 NMR DMSOd6 (˜ 55°) 8-13 δ (v. broad, OH, N.sup.⊕ H3), 9.96 (s, 2, CONH), 7.80 (m, 4, H-1,3), 7.56 (m, 2, H-2), 5.35 (bs, 2, OH), 5.25 (bs, 2, H-1'), 5.04 (bs, 2, OH), 4.74 (m, 2, H-7), 4.12 (m, 2, H-5'), 3.97 (s, 6, OCH3), 3.64 (bs, 2, H-4'), 3.40 (m, 2, H-3'), 3.22 (bs, H2 O), 2.98 (bs, 4, H-10), 2.30 (m, 8, H-8, COCH2 (CH2)2 CH2 CO), 1.95 (s, 6, H-14), 1.80 (bs, 4, H-2'), 1.49 (bs, 4, COCH2 (CH2)2 CH2 CO), 1.18 (d, 6, J=6Hz, CH3 -5'). [α]D 22 ° = +247° (c, 0.047, EtOH). Tlc on SiGF in CHCl3 /CH3 OH/2.0 N AcOH (10/5/1) (XII) Rf 0.56, (III) Rf 0.30. Paper chromatography in n-PrOH/H2 O (4/1) (XII) Rf 0.63, (III) Rf 0.30; in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.75, (III) Rf 0.69.
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Anal. Calcd. for C.sub.60 H.sub.68 N.sub.6 O.sub.20 ·2HCl.multido
t.2 1/2 H.sub.2 O
C H Cl.sup.θ
N
______________________________________
54.96 5.77 5.41 6.41
Found: 55.02 5.48 5.19 6.30
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A mixture of 0.406 g (0.72 mmol) of daunomycin hydrochloride and 0.073 g (0.36 mmol) of suberic acid dihydrazide in 70 ml of methanol was stirred at room temperature in the dark for 3 days. After concentrating to 35 ml, the reaction mixture was stirred at room temperature for an additional 8 days. To the stirred solution was then added 35 ml of ether dropwise; the resulting precipitate was collected, washed with 3-10 ml portions of ether and dried at room temperature /0.1 mm/18 hr to afford 0.407 g (85%) of the bis-hydrazone dihydrochloride (IV), mp 229°-232° dec. IR (Nujol) 2.82, 3.02 μm (OH), 5.99 (C═O, hydrazone), 6.20, 6.31 (C═O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε = 85,300), 250 sh (53,500), 289 (15,300), 484-492 plateau (20,500), 498 (20,800), 535 (12,200). XL-100NMR DMSOd6 (˜ 55°) 8-12 δ (v. broad, N.sup. ⊕ H3 OH), 9.82 (s, 2, CONH), 7.80 (m, 4, H- 1,3), 7.59 (m, 2, H-2), 5.27 (bs, 2, H-1'), 5.17 (bs, 4, OH), 4.78 (bs, 2, H-7), 4.10 (m, 2, H-5'), 3.97 (s, 6, OCH3), 3.64 (bs, 2, H-4'), 3.36 (m, 2, H-3'), 3.21 (d, 2, J=19Hz H-10B), 3.20 (bs, H2 O), 2.90 (d, 2, J=19Hz H-10A), 2.26 (m, 8 COCH2 (CH2)4 CH2 CO,H-8), 1.93 (s, 6, H-14), 1.82 (bs, 4, H-2'), 1.35 (m, 8, COCH2 (CH2)4 CH2 CO), 1.18 (d, 6, J=6HzCH3 -5'). [α]D 21° = +273° (c 0.053, EtOH). Tlc on SiGF in CHCl3 /CH3 OH/2.0 N AcOH (10/5/1) (XII) Rf 0.57, (IV) Rf 0.34. Paper chromatography in n-PrOH/H2 O (4/1) (XII) Rf 0.71, (IV) Rf 0.44; in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.76, (IV) Rf 0.68.
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Anal. Calcd. for C.sub.62 H.sub.72 N.sub.6 O.sub.20 ·2HCl.multido
t.2H.sub.2 O
C H Cl.sup.θ
N
______________________________________
55.98 5.91 5.33 6.32
Found: 55.96 5.75 5.28 6.27
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A mixture of 0.406 g (0.72 mmol) of daunomycin hydrochloride and 0.083 g (0.36 mmol) of sebacic acid dihydrazide in 165 ml of methanol was stirred at room temperature in the dark. At intervals, the reaction mixture was concentrated in the following manner: after 4 days to 70 ml, after 9 days to 35 ml, after 11 days to 21 ml, and after 28 days to 14 ml. After 35 days, an additional 0.008 g (0.036 mmol) of sebacic acid dihydrazide was added to the reaction mixture. After 42 days, the reaction mixture was diluted with 14 ml of ether added dropwise. The resulting precipitate was collected, washed with 5-10 ml portions of ether and dried at room temperature/0.1 mm/15 hr to give 0.419 g (87%) of the bis-hydrazone dihydrochloride (V), mp 211°-215° dec. IR (Nujol) 2.82, 3.14 μm (OH), 6.00 (C═ O, hydrazone), 6.18, 6.30 (C═O, chelated quinone). UV-Vis max (CH3 OH) 234 nm (ε = 82,600), 250 sh (53,700), 288 (14,900), 481 (20,600), 488-497 plateau (20,400), 533 sh (11,900). XL-100 NMR DMSOd6 (˜ 50°) 8-11 δ (v. broad, N.sup.⊕ H3, OH), 9.86 (bs, 2, CONH), 7.79 (m, 4, H-1,3), 7.58 (m, 2, H-2), 5.28 (bs, 4, H-1', OH), 4.76 (m, 2, H-7), 4.07 (m, 2, H-5'), 3.95 (s, 6, OCH3), 3.62 (bs, 2, H-4'), 3.37 (m, 2, H-3'), 3.20 (bs, 2, H-10B), 2.82 (d, 2, J=19Hz, H-10A), 2.21 (m, 8, H-8, COCH2 (CH2)6 CH2 CO), 1.92 (s, 6, H-14), 1.82 (m, 4, H-2'), 1.19 (d, 6, J=6Hz CH3 - 5'), 1.00 (bs, 12, COCH2 (CH2)6 CH2 CO). [α]D = +260° (c, 0.049, EtOH. Tlc on SiGF in CHCl3 /CH3 OH/2.0 N AcOH (10/5/1) (XII) Rf 0.52, (V) Rf 0.31. Paper chromatography in n-PrOH/H2 O (4/1) (XII) Rf 0.71, (V) Rf 0.56; in n-BuOH/AcOH/H2 O (5/2/3), (XII) Rf 0.76, (V) Rf 0.59.
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Anal. Calcd. for C.sub.64 H.sub.76 N.sub.6 O.sub.20 ·2HCl.multido
t.H.sub.2 O
C H Cl.sup.θ
N
______________________________________
57.35 6.02 5.29 6.27
Found: 57.30 5.90 4.86 6.31
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A mixture of 0.374 g (0.6 mmol) of N,N-dimethyldaunomycin hydrochloride 1 3/4 hydrate and 0.0438 g (0.3 mmol) of succinic acid dihydrazide in 36 ml of methanol was stirred at room temperature in the dark for 2 days. After concentrating to 12 ml, the reaction mixture was stirred at room temperature for 5 additional days and then was diluted with 18 ml of ether added dropwise. The resulting precipitate was collected, washed with 3-10 ml portions of ether and dried at room temperature/0.1 mm/16 hr to yield 0.367 g (91%) of the bis-hydrazone (VI), mp 194°-196°. IR (Nujol) 2.98 μm (OH), 3.70 (HN.sup.⊕ (CH3)2), 5.98 (C═O, hydrazone), 6.18, 6.31 (C═O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε = 89,900), 250 sh (56,700), 288 (15,400), 478 (22,200), 494 sh (21,200), 531 sh (11,800). XL-100 NMR DMSOd6 (˜ 55°) 13.99 δ (s, 2, OH-6), 13.20 (s, 2, OH-11), 9.90 (bs, 2. HN.sup.⊕ (CH3)2), 9.74 (bs, 2, CONH), 7.79 (m, 4, H-1,3), 7.57 (m, 2, H-2), 5.57 (d, 2, J=6Hz, OH-4'), 5.41 (s, 2, H-1'), 5.15 (s, 2, OH-9), 4.91 (m, 2, H-7), 4.05 (m, 2, H-5'), 3.96 (s, 6, OCH3), ˜ 3.9 (m, 2, H-3'), 3.40 (m, 2, H-4'), 3.21 (s, H2 O), 3.07 (bs, 2, H-10B), 2.87 (bs, 2, H-10A), 2.75 (s, 12, N.sup.⊕ (CH3)2), 2.30 (m, 8, H-8, COCH2 CH2 CO), 2.00 (m, 4, H-2'), 1.87 (s, 6, H- 14), 1.19 (d, 6, J=6Hz, CH3 -5'). [α]D = +198° (c 0.051, EtOH). Tlc on SiGF in CHCl3 /CH3 OH/2.0 N AcOH (10/5/1) starting material Rf 0.48, (VI) Rf 0.28. Paper chromatography in n-PrOH/H2 O (4/1) starting material Rf 0.78, (VI) Rf 0.31; in n-BuOH/AcOH/H2 O (5/2/3) starting material Rf 0.75, (VI) Rf 0.66.
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Anal. Calcd. for C.sub.62 H.sub.72 N.sub.6 O.sub.20 ·2HCl.multido
t.3H.sub.2 O
C H Cl.sup.θ
N
______________________________________
55.23 5.98 5.26 6.23
Found: 55.06 5.74 4.87 6.27
______________________________________
A solution of 1.16 g (2.0 mmol) of adriamycin hydrochloride (XI) and 0.146 g (1.0 mmol) of succinic acid dihydrazide in 400 ml of methanol was stirred at room temperature in the dark. The reaction mixture was concentrated at intervals in the following manner: after 3 days to 200 ml, after 6 days to 100 ml, after 10 days to 50 ml, and after 14 days to 25 ml. After 22 days, an additional 0.015 g (0.1 mmol) of succinic acid dihydrazide was added to the reaction mixture. After 44 days, the reaction mixture was slowly diluted with 25 ml of ether; the resulting precipitate was collected, washed with ether and dried at room temperature/0.1 mm/15 hr to afford 1.22 g of (VII) containing 5-7% adriamycin hydrochloride (XI). A 0.608 g sample of crude (VII) in 10 ml of methanol was applied on a 2.5 × 90 cm (˜ 440 ml) column of Sephadex LH-20 (packed and washed with methanol). The column was eluted with methanol and 5.0 ml fractions were collected. Fractions No. 41-54 were combined and evaporated to yield 0.536 g of (VII). A second 0.607 g sample of crude (VII) was purified in a similar manner. The combined sample (0.961 g) of purified (VII) was dissolved in 20 ml of methanol and the solution was stirred and diluted with 20 ml of ether added dropwise. The resulting precipitate was collected, washed with 3-10 ml portions of ether and dried at room temperature/0.1 mm/20 hr to give 0.930 g (68%) of the bis-hydrazone dihydrochloride (VII), mp - gradually decomposes from 210°. IR (Nujol) 3.05 μm (OH), 6.00 (C═O, hydrazone), 6.18, 6.32 (C═O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε = 86,000), 246 sh (59,400), 288 (15,800), 478 (21,900), 489 sh (21,200), 530 sh (11,700). XL-100 NMR DMSOd6 (˜ 55°), 8-12 δ (v. broad N.sup.⊕ H3, OH), 10.23 (bs, 2, CONH), 7.80 (m, 4, H-1,3), 7.55 (m, 2, H-2), 5.75 (bs, 2, OH), 5.31 (bs, 2, H-1'), ˜ 5.3 (bs, 2, OH), 5.17 (bs, 2, OH), 4.91 (m, 2, H-7), 4.43 (bs, 4, H-14), 4.09 (m, 2, H-5'), 3.96 (s, 6, OCH3), 3.63 (bs, 2, H-4'), 3.40 (m, 2, H-3'), 3.21 (s, H2 O), 3.05 (d, 2, J=19Hz, H-10B), 2.94 (d, 2, J=19Hz, H-10A), 2.31 (m, 4, H-8), 1.83 (m, 4, H-2'), 1.19 (d, 6, J=6Hz, CH3 -5'). [α]D = +232° (c 0.05, EtOH). Tlc on SiGF in CHCl3 /CH3 OH/H2 O (20/10/1), (XI) Rf 0.32, (VII) Rf 0.03; in CHCl3 /CH3 OH/2.0 N AcOH (10/5/1) (XI) Rf 0.43, (VII) Rf 0.17. Paper chromatography in n-PrOH/H2 O (4/1) (XI) Rf 0.47, (VII) Rf 0.05; in n-BuOH/AcOH/H2 O (5/2/3) (XI) Rf 0.62, (VII) Rf 0.56.
______________________________________
Anal. Calcd. for C.sub.58 H.sub.64 N.sub.6 O.sub.22 ·2HCl.multido
t.5H.sub.2 O
C H Cl.sup.θ
N
______________________________________
51.22 5.63 5.21 6.18
Found: 51.21 5.27 5.13 6.36
______________________________________
A solution of 0.339 g (0.6 mmol) of daunomycin hydrochloride and 0.0396 g (0.3 mmol) of malonyl dihydrazide in 24 ml of methanol was stirred in the dark at room temperature. After 14 days, the reaction mixture was concentrated to 12 ml and then 25 ml of ether were added dropwise. The resulting precipitate was collected, washed with 5--5 ml portions of ether and dried at room temperature /0.1 mm/16 hr to afford 0.351 g (93%) of the malonylhydrazone (VIII), mp dec. 225°-240°. IR (Nujol) 2.92 μm (OH), 5.92 (C═N), 6.17, 6.31 (C═O, chelated quinone). UV-Vis max (CH3 OH) 234 nm (ε 75,200), 250 sh 848,400), 287 (12,900), 483 (18,400), 493-499 plateau (17,900), 535 sh (10,300). XL-100 NMR DMSOd6 (˜ 55°) 8-12 δ (v. board, OH, N.sup.⊕ H3), 10.15 (s, 2, CONH), 7.72 (m, 4, H-1,3), 7.47 (m, 2, H-2), 5.29 (bs, 2, OH), 5.21 (bs, 2, H-1'), 4.87 (bs, 2, OH), 4.75 (bs, 2, H-7), 4.10 (m, 2, H-5'), 3.95 (s, 6, OCH3), 3.61 (bs, 4, COCH2 CO, H-4'), 3.37 (m, 2, H-3'), 3.23 (bs, H2 O), 2.83 (bs, 4, H-10), 2.19 (m, 4, H-8), 1.92 (s, 6, H-14), 1.77 (m, 4, H-2'), 1.13 (d, 6, J=6Hz, CH3 -5'). [α]D 21° = +230° (c 0.053, EtOH). Tlc on SiGF in CHCl3 /CH3 OH. 2 N AcOH (10/5/1/) (XII) Rf 0.56, (VIII) Rf 0.17. Paper chromatography in n-PrOH/H2 O (4:1): (XII) Rf 0.56, (VIII) Rf 0.09; in n-BuOH/AcOH/H2 O (5/2/3): (XII) Rf 0.79, (VIII) Rf 0.71.
______________________________________
Anal. Calcd. for C.sub.57 H.sub.62 N.sub.6 O.sub.20 ·2HCl.multido
t.1 1/2 H.sub.2 O
C H Cl.sup.θ
N
______________________________________
54.72 5.40 5.67 6.72
Found: 54.84 5.59 5.43 6.71
______________________________________
A suspension of 0.564 g (1.0 mmol) of daunomycin hydrochloride and 0.059 g (0.5 mmol) of oxalyl dihydrazide in 200 ml of methanol was stirred at room temperature in the dark. After 15 days, the homogenous reaction mixture was concentrated to 100 ml and stirred at room temperature for an additional 40 days. The reaction mixture was concentrated to 50 ml and then 75 ml of absolute ethanol was added dropwise. The resulting fine gelatinous precipitate was collected by centrifugation (3000 X g); the precipitate was transferred to a fritted disc funnel and washed with 2--2 ml portions of absolute ethanol and with 5 ml of ether. After drying at room temperature, the precipitate was powdered well and redried at room temperature /0.1 mm/17 hr to afford 0.459 g (73%) of the bis-hydrazone dihydrochloride (IX), mp gradually dec. 220°-240°. IR (Nujol) 2.90, 3.04 μm (OH), 5.99 (C═O, hydrazone), 6.16, 6.29 (C═ O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε = 83,200), 249 (57,700), 284 sh (17,400), 478 (22,700), 496 (22,000), 531 sh (12,000). XL-100 NMR DMSOd6 (˜ 50°) 6-12 δ (v. broad, N.sup.⊕ H3, OH), 10.50 (bs, 2, CONH), 7.82 (m, 4, H-1,3), 7.63 (m, 2, H-2), 5.29 (bs, 4, H-1', OH), 4.89 (m, 2, H-7), 4.13 (m, 2, H-5'), 3.98 (s, 6, OCH3), 3.61 (bs, 2, H-4'), 3.34 (m, 4, H-10B, H-3'), 3.18 (s, H2 O), 2.89 (d, 2, J=19Hz, H-10A), 2.20 (m, 4, H-8), 1.94 (s, 6, H-14), 1.80 (m, 4, H-2'), 1.17 ("bs," 6, CH3 -5'). [α]D 21° = +261° (c 0.046, CH3 OH). Tlc on SiGF CHCl3 /CH3 OH/2 N AcOH (10/5/1) (XII) Rf 0.49, (IX) Rf 0.20. Paper chromatography in n-PrOH/H2 O (4/1): (XII) Rf 0.66 (IX) Rf 0.02; in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.73, (IX) Rf 0.68.
______________________________________
Anal. Calcd. for C.sub.56 H.sub.60 N.sub.6 O.sub.20 ·2HCl.multido
t.2 1/2 H.sub.2 O (1255.08)
C H Cl.sup.θ
N
______________________________________
53.59 5.38 5.65 6.70
Found: 53.56 5.51 5.45 6.44
______________________________________
A mixture of 0.452 g (0.8 mmol) of daunomycin hydrochloride and 0.0753 g (0.4 mmol) of pimelyl dihydrazide in 50 ml of methanol was stirred at room temperature in the dark for 7 days during which time the bis-hydrazone (X) precipitated. The precipitate was collected, washed with 5-1 ml portions of methanol and with 3-5 ml portions of ether and dried at room temperature. The precipitate was powdered well and redried at room temperature /0.1 mm/17 hr to give 0.373 g (71%) of the bis-hydrazone (X), mp 239°-242° dec. IR (Nujol) 2.80, 3.08 μm (OH), 6.00 (C═O, hydrazone), 6.16, 6.29 (C═O, chelated quinone). UV-Vis max (CH3 OH) 233 nm (ε 85,800), 250 sh (54,200), 290 (16,200), 486 (21,300), 499 (21,400), 536 sh (12,300). XL-100 NMR DMSOd6 (˜ 50°) 8-12 δ (v. broad, N.sup.⊕ H3, OH), 9.81 (s, 2, CONH), 7.81 (m, 4, H-1,3), 7.58 (m, 2, H-2), 5.25 (bs, 4, H- 1', OH), 5.15 (bs, 2, OH), 4.83 (m, 2, H-7), 4.10 (m, 2, H-5'), 3.96 (s, 6, OCH3), 3.64 (bs, 2, H4'), 3.24 ("m," 4, H-3', H-10B), 3.19 (bs, H2 O), 2.81 ("d," 2, J=19Hz, H-10A), 2.25 (m, 8, H-8, COCH2 (CH2)3 CH2 CO) 1.94 (s, 6, H-14), 1.81 (m, 4, H-2'), 1.32 (m, 6, COCH2 (CH2)3 CH2 CO), 1.19 (d, 6, J=6Hz, CH3 -5'). [α]D 21° = +239°(c 0.054, CH3 OH). Tlc on SiGF CHCl3 /CH3 OH/2 N AcOH (10/5/1 ) (XII) Rf 0.50, (X) Rf 0.23. Paper chromatography in n-PrOH/H2 O (4/1) (XII) Rf 0.66 (X) Rf 0.27; in n-BuOH/AcOH/H2 O (5/2/3) (XII) Rf 0.73, (X) Rf 0.68.
______________________________________
Anal. Calcd. for C.sub.61 H.sub.70 N.sub.6 O.sub.20 ·2HCl.multido
t.1 1/2 H.sub.2 O (1307.21)
C H Cl.sup.θ
N
______________________________________
56.05 5.78 5.42 6.43
Found: 55.89 5.47 5.36 6.47
______________________________________
Biological testing data for compounds of this invention as the HCl salts, as well as for adriamycin and daunomycin, are presented in the table given below. The compounds were tested first in cultured lymphoid leukemia L1210 cells for inhibition of nucleic acid synthesis by previously reported procedures. The analogs were then tested against lymphocytic leukemia P388 implanted in mice, under the auspices of the NCI and according to its protocols which use the increased survival time of treated mice compared to controls as the measure of antitumor efficacy.
__________________________________________________________________________
Bioassay Data on Bis-hydrazones of
Daunomycin and Adriamycin
Vs Cultured L1210 Leukemia Cells.sup.b
Vs P388 Leukemia in Mice.sup.c
Inhibition of Synthesis
Optimum
Antitumor
Optimum Dose
NSC.sup.a
of DNA of RNA
Dose, qd 1-9
Efficacy
q4d5,9,13
Antitumor Efficacy
Compound
No. ED.sub.50, μM
Ed.sub.50, μM
mg/kg T/C, %
mg/kg T/C,%
__________________________________________________________________________
I 266210
13 3.4 6.25 283.sup.d
20 170
12.5 307.sup.e
II 266211
4.5 3.6 1.56 188
no data--
3.12 149
III 273432
8.9 3.6 6.25 281,289
37.5 196
IV 276747
4.9 2.4 8 245 25 178
V 276748
10 1.0 12.5 221 50 163
VI 274885
19 3.0 4 178 25 158
VII 273433
13.3 3.1 6.25 309 18.8 160
VIII 279510
14.1 7.4 6.25 169 (inactive)
IX 285695
4.3 2.3 25 160
X 285696
2.0 1.3 25 160
Adriamycin
123127
1.5 0.67 1.0 195 8 157
Daunomycin
82151
0.49 0.39 0.5 166 8 134
__________________________________________________________________________
.sup.a Accession number of the National Cancer Institute.
.sup.b Assay described in G. Tong, W. W. Lee, D. R. Black and D. W. Henry
J. Med. Chem., 19 395 (1976).
.sup.c Ip P388 murine leukemia treated ip on QD1-9 and Q4D 5, 9, 13
schedules according to standard NCI protocols. Assay described in R. I.
Geran, N. H. Greenberg, M. M. MacDonald, A. M. Schumacker and B. J.
Abbott, Cancer Chemother. Rep., Part 3, 3 (No. 2), 9 (1972), Protocol
1,200. T/C = ratio of survival time of treated mice to that of untreated
controls times 100. Untreated controls survive about 9 days.
.sup.d Three out of six treated mice survived until sacrifice at 30 days.
.sup.e Two out of six treated mice survived until sacrifice at 45 days.
Claims (11)
1. Compounds having the structure ##STR3## wherein n is an integer having a value of from 0 through 8 and the radicals indicated by R and R' each represent hydrogen except that in those instances in which n has a value of 2, the R groups, if not hydrogen, may be methyl radicals (with R' remaining as hydrogen), and the R' groups, if not hydrogen, may be hydroxy radicals (with R remaining as hydrogen), together with their pharmaceutically acceptable acid addition salts.
2. The compound of claim 1 in which is bis(daunomycin) succinylhydrazone together with its pharmaceutically acceptable acid addition salts.
3. The compound of claim 1 which is bis(daunomycin) glutarylhydrazone together with its pharmaceutically acceptable acid addition salts.
4. The compound of claim 1 which is bis(daunomycin) adipylhydrazone together with its pharmaceutically acceptable acid addition salts.
5. The compound of claim 1 which is bis(daunomycin) suberylhydrazone together with its pharmaceutically acceptable acid addition salts.
6. The compound of claim 1 which is bis(daunomycin) sebacylhydrazone together with its pharmaceutically acceptable acid addition salts.
7. The compound of claim 1 which is bis(N,N-dimethyldaunomycin) succinylhydrazone together with its pharmaceutically acceptable acid addition salts.
8. The compound of claim 1 which is bis(adriamycin) succinylhydrazone together with its pharmaceutically acceptable acid addition salts.
9. The compound of claim 1 which is bis(daunomycin) malonylhydrazone together with its pharmaceutically acceptable acid addition salts.
10. The compound of claim 1 which is bis(daunomycin) oxalylhydrazone together with its pharmaceutically acceptable acid addition salts.
11. The compound of claim 1 which is bis(daunomycin) pimelylhydrazone together with its pharmaceutically acceptable acid addition salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/830,091 US4112217A (en) | 1977-09-02 | 1977-09-02 | Bis-hydrazones of daunomycin and adriamycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/830,091 US4112217A (en) | 1977-09-02 | 1977-09-02 | Bis-hydrazones of daunomycin and adriamycin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4112217A true US4112217A (en) | 1978-09-05 |
Family
ID=25256292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/830,091 Expired - Lifetime US4112217A (en) | 1977-09-02 | 1977-09-02 | Bis-hydrazones of daunomycin and adriamycin |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US4112217A (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004467A2 (en) * | 1978-03-24 | 1979-10-03 | The Regents Of The University Of California | Bis-anthracyclines, methods of making and using them and liposome compositions for administering them |
| US4275192A (en) * | 1979-05-03 | 1981-06-23 | G. D. Searle & Co. | Bis(4-demethoxydaunorubicin)dihydrazone derivatives and pharmacologically acceptable salts thereof |
| US4291157A (en) * | 1980-07-22 | 1981-09-22 | Sri International | Octanoylhydrazone derivatives of adriamycin |
| DE3037884A1 (en) * | 1980-03-24 | 1981-10-01 | Institut chimičeskoj fiziki Akademii Nauk SSSR, Moskva | 13- (1-OXYL-2,2,6,6-TETRAMETHYL-PIPERYLIDENYL-4) HYDRAZONE-RYBOMYZINE HYDROCHLORIDE WITH A PARAMAGNETIC CENTER AND METHOD FOR THE PRODUCTION THEREOF |
| US4950738A (en) * | 1984-09-13 | 1990-08-21 | Cytogen Corporation | Amine derivatives of anthracycline antibiotics |
| EP0398305A2 (en) * | 1989-05-17 | 1990-11-22 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
| US5122368A (en) * | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
| US5137877A (en) * | 1990-05-14 | 1992-08-11 | Bristol-Myers Squibb | Bifunctional linking compounds, conjugates and methods for their production |
| US5162512A (en) * | 1982-03-09 | 1992-11-10 | Cytogen Corporation | Amine derivatives of anthracycline antibodies |
| US5824805A (en) * | 1995-12-22 | 1998-10-20 | King; Dalton | Branched hydrazone linkers |
| US5874412A (en) * | 1996-03-22 | 1999-02-23 | Priebe; Waldemar | Bis-anthracyclines with high activity against doxorubicin resistant tumors |
| CN102399249A (en) * | 2011-11-28 | 2012-04-04 | 河南师范大学 | 13-glycosyl oxime ether-3'-azido daunorubicin new compound with anti-cancer activity and preparation method thereof |
| CN102603824A (en) * | 2011-12-15 | 2012-07-25 | 河南师范大学 | New 3'-azido daunorubicin-13-thiosemicarbazone compound with cancer resistance and preparation method thereof |
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| US3957755A (en) * | 1967-10-18 | 1976-05-18 | Rhone-Poulenc S.A. | Naphthacene derivatives |
| US3965088A (en) * | 1967-10-18 | 1976-06-22 | Rhone-Poulenc S.A. | Naphthacene derivatives |
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| US3957755A (en) * | 1967-10-18 | 1976-05-18 | Rhone-Poulenc S.A. | Naphthacene derivatives |
| US3965088A (en) * | 1967-10-18 | 1976-06-22 | Rhone-Poulenc S.A. | Naphthacene derivatives |
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Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004467A3 (en) * | 1978-03-24 | 1980-01-09 | The Regents Of The University Of California | Bis-anthracyclines, methods of making and using them, liposome compositions for administering them and methods of making such compositions |
| US4263428A (en) * | 1978-03-24 | 1981-04-21 | The Regents Of The University Of California | Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same |
| EP0004467A2 (en) * | 1978-03-24 | 1979-10-03 | The Regents Of The University Of California | Bis-anthracyclines, methods of making and using them and liposome compositions for administering them |
| US4275192A (en) * | 1979-05-03 | 1981-06-23 | G. D. Searle & Co. | Bis(4-demethoxydaunorubicin)dihydrazone derivatives and pharmacologically acceptable salts thereof |
| DE3037884A1 (en) * | 1980-03-24 | 1981-10-01 | Institut chimičeskoj fiziki Akademii Nauk SSSR, Moskva | 13- (1-OXYL-2,2,6,6-TETRAMETHYL-PIPERYLIDENYL-4) HYDRAZONE-RYBOMYZINE HYDROCHLORIDE WITH A PARAMAGNETIC CENTER AND METHOD FOR THE PRODUCTION THEREOF |
| US4291157A (en) * | 1980-07-22 | 1981-09-22 | Sri International | Octanoylhydrazone derivatives of adriamycin |
| US5162512A (en) * | 1982-03-09 | 1992-11-10 | Cytogen Corporation | Amine derivatives of anthracycline antibodies |
| US4950738A (en) * | 1984-09-13 | 1990-08-21 | Cytogen Corporation | Amine derivatives of anthracycline antibiotics |
| US5122368A (en) * | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
| EP0398305A2 (en) * | 1989-05-17 | 1990-11-22 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
| EP0398305A3 (en) * | 1989-05-17 | 1991-03-20 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
| US5137877A (en) * | 1990-05-14 | 1992-08-11 | Bristol-Myers Squibb | Bifunctional linking compounds, conjugates and methods for their production |
| US5349066A (en) * | 1990-05-14 | 1994-09-20 | Bristol-Myers Squibb Company | Bifunctional linking compounds, conjugates and methods for their production |
| US5824805A (en) * | 1995-12-22 | 1998-10-20 | King; Dalton | Branched hydrazone linkers |
| US6512101B1 (en) * | 1995-12-22 | 2003-01-28 | Bristol Myers Squibb Company | Branched hydrazone linkers |
| US5874412A (en) * | 1996-03-22 | 1999-02-23 | Priebe; Waldemar | Bis-anthracyclines with high activity against doxorubicin resistant tumors |
| EP0971716A1 (en) * | 1996-03-22 | 2000-01-19 | Waldemar Priebe | Bis-anthracyclines with high activity against doxorubicin resistant tumors |
| EP0971716A4 (en) * | 1996-03-22 | 2000-01-19 | Waldemar Priebe | Bis-anthracyclines with high activity against doxorubicin resistant tumors |
| CN102399249A (en) * | 2011-11-28 | 2012-04-04 | 河南师范大学 | 13-glycosyl oxime ether-3'-azido daunorubicin new compound with anti-cancer activity and preparation method thereof |
| CN102603824A (en) * | 2011-12-15 | 2012-07-25 | 河南师范大学 | New 3'-azido daunorubicin-13-thiosemicarbazone compound with cancer resistance and preparation method thereof |
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